This is a revised application for an independent research award by a new investigator originally reviewed by the RPIA study section in March 2007 (1R01DA023579-01). We will use functional magnetic resonance imaging (fMRI) to compare the hemodynamic and behavioral responses to a drug Stroop task, a newly developed task of Impaired Response Inhibition and Salience Attribution, between cocaine addicted individuals and healthy control subjects (Aim 1). We will compare these fMRI results with and without oral methylphenidate (MPH), a dopamine agonist, used here to enhance the salience of the drug-related cues (Aim 2). Finally, we will use this pharmacological fMRI results to predict relapse at 180-day follow-up in initially abstinent cocaine addicted subjects (Aim 3). We have 3 main hypotheses: (1) compared to controls, cocaine addicted individuals will attribute more salience to drug-related words than to matched neutral words as measured with enhanced hemodynamic responses of the prefrontal cortex (PFC) and striatum, increased behavioral impulsivity and higher self-reported drug wanting (i.e., craving). (2) oral MPH, a stimulant drug that similarly to cocaine blocks dopamine transporters and increases extracellular dopamine, will enhance the activity in the PFC leading to enhanced salience attributed to the drug-related words on the drug Stroop task. And (3) the higher the drug-related interference on the drug Stroop task at baseline (especially during the MPH challenge), the faster the time to relapse or the more severe the relapse at follow-up. Using this pharmacological fMRI design we will thus indirectly assess the involvement of dopamine in the excessive salience attribution and impulsivity in a drug-related context in drug addicted individuals. A better understanding of the changes in the brain of addicted subjects with respect to drug cues and their enhanced salience by a stimulant drug will help develop behavioral or pharmacological interventions that may be beneficial in counteracting the overpowering salience of drug related cues (and possibly in increasing salience of non-drug cues) in drug addicted individuals to minimize craving, enhance self-control, and prevent relapse. The major changes since the previous submission include: addition of preliminary results that now demonstrate (1) that the drug Stroop fMRI task induces a unique behavioral interference in the cocaine addicted subjects; and (2) feasibility to conduct this particular pharmacological study in our selected subject groups; other changes include the (3) publication of our prior fMRI studies in cocaine addicted individuals; and (4) other clarifications in response to specific concerns raised by the reviewers (e.g., inclusion of current cocaine users as an active control group to enhance interpretability of results; inclusion of perfusion MRI to address concerns about effect of MPH on cerebral blood flow; and other clarifications and changes related to MPH sensitization and expectation, practice effects, subject exclusion and matching, relapse assessment, and the study of other key brain regions such as the insula). The proposal in its current form is consequently substantially improved. PUBLIC HEALTH RELEVANCE The results of this project may be of therapeutic relevance and contribute to the design and implementation of new specialized intervention and treatment programs to maximize the likelihood of treatment success and minimize relapse, which remains the primary problem in treating drug abuse. Thus, using the pharmacological functional activation and behavioral results in our study, we may be able to highlight the intervention approaches that may be most beneficial.